A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease.

OBJECTIVE: Gaucher disease (GD) is a rare disorder linked to the absence/deficiency of glucocerebrosidase. GD can be treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The aim of this systematic review (SR) is to assess the effectiveness of drugs used for GD treatment. DATA SOURCES: Searches were conducted in PubMed and Scopus, in April 2021. The search strategies encompassed the name of the disease and of the drug treatments. Manual search was also conducted. STUDY SELECTION AND DATA EXTRACTION: Observational and interventional longitudinal studies evaluating ERT and SRT for GD were included. Single mean meta-analyses were conducted for each drug using R. DATA SYNTHESIS: The initial search retrieved 2246 articles after duplicates were removed. Following screening and eligibility assessment, 68 reports were included. The studies evaluated imiglucerase, velaglucerase alfa, taliglucerase alfa, miglustat, and eliglustat. The results showed that ERT is effective as a treatment in both naïve and experienced patients. Miglustat did not significantly improve blood outcomes in naïve patients and resulted in a decrease in the platelet levels of experienced patients. Eliglustat was mainly assessed for experienced patients and resulted in stable outcome values. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This extensive SR confirms the effectiveness of GD treatments in short- and long-term follow-ups. CONCLUSIONS: The results were favorable for all ERTs and for eliglustat. Based on the assessed evidence, miglustat did not achieved expressive results. However, all evidence should be interpreted considering its limitations and does not replace well-conducted randomized trials.

Systematic review with network meta-analysis on the treatments for latent tuberculosis infection in children and adolescents.

BACKGROUND: We aimed to synthesize the evidence on the efficacy and safety of different treatment regimens for latent tuberculosis infection (LTBI) in children and adolescents. METHODS: A systematic review with network meta-analysis was performed (CRD142933). Searches were conducted in Pubmed and Scopus (Nov-2021). Randomized controlled trials comparing treatments for LTBI (patients up to 15 years), and reporting data on the incidence of the disease, death or adverse events were included. Networks using the Bayesian framework were built for each outcome of interest. Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Rank probabilities were calculated via the surface under the cumulative ranking analysis (SUCRA) (Addis-v.1.16.8). GRADE approach was used to rate evidence's certainty. RESULTS: Seven trials (n = 8696 patients) were included. Placebo was significantly associated with a higher incidence of tuberculosis compared to all active therapies. Combinations of isoniazid (15-25 mg/kg/week) plus rifapentine (300-900 mg/week), followed by isoniazid plus rifampicin (10 mg/kg/day) were ranked as best approaches with lower probabilities of disease incidence (10% and 19.5%, respectively in SUCRA) and death (20%). Higher doses of isoniazid monotherapy were significantly associated to more deaths (OR 18.28, 95% ICr [1.02, 48.60] of 4-6 mg/kg/day vs. 10 mg/kg/3x per week). CONCLUSIONS: Combined therapies of isoniazid plus rifapentine or rifampicin for short-term periods should be used as the first-line approach for treating LTBI in children and adolescents. The use of long-term isoniazid as monotherapy and at higher doses should be avoided for this population.

Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis.

PURPOSE: To quantitatively assess the benefit-risk ratio on the efficacy and safety of all phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction. METHODS: A systematic review with network meta-analysis, surface under the cumulative ranking analysis and stochastic multicriteria acceptability analyses were performed. Searches were conducted in Pubmed, Scopus, Web of Science without limits for time-frame or language. Randomized controlled trials evaluating the efficacy or safety of any PDE5i compared to a placebo or to other PDE5i in males with erectile disfunction were included. RESULTS: Overall, 184 articles representing 179 randomized controlled trials (50,620 patients) were included. All PDE5i were significantly more efficient than placebo. Sildenafil 25 mg was statistically superior to all interventions in enhancing IIEF (with a 98% probability of being the most effective treatment), followed by sildenafil 50 mg (80% of probability). Taladafil 10 mg and 20 mg also presented good profiles (73% and 76%, respectively). Avanafil and lodenafil were less effective interventions. Mirodenafil 150 mg was the treatment that caused more adverse events, especially flushing and headaches. Sildenafil 100 mg was more related to visual disorders, while vardenafil and udenafil were more prone to cause nasal congestion. CONCLUSION: Sildenafil at low doses and tadalafil should be the first therapeutic options. Avanafil, lodenafil and mirodenafil use are hardly justified given the lack of expressive efficacy or high rates of adverse events.

Five-year survival analysis and predictors of death in HIV-positive serology patients attending the Military Hospital of Nampula, Mozambique.

An observational retrospective study was conducted over a 5-year period to assess survival and predictors of death in people with HIV-positive serology undergoing antiretroviral treatment with first-line regimens at the Military Hospital of Nampula, Mozambique. We collected data from 332 patient records. Kaplan-Meier boundary product estimator, log-rank, Gehan-Breslow, Tarone-Ware, time-dependent Cox models and estimates of hazard ratios (HR), with 95% confidence interval (CI) were calculated. Meantime survival for females and males was 54.8 months [95% CI 50.32-55.40] and 49.7 months [95% CI 45.89-53.53], respectively. Cox regressions indicated higher death rates significantly or potentially associated with: male sex (HR = 1.3; [95% CI 0.7-2.39]); suspected diagnosis reported only by the physician (HR = 3.6; [95% CI 1.8-7.4]); disease stages III (HR=1.2 [95% CI 0.3-3.6]) or IV (HR 1.4 [95% CI 0.4-5.8]); first TCD4+ lymphocyte count lower than 350 cells per ml (HR = 3.2; [95% CI 0.9-11.2]) or between 350-500 cells per ml (HR = 1.3; [95% CI 0.3-5.8]); or do not present cells count (HR = 3.6; [95% CI 1.2-10.2]). The above variables were significant for HIV prognosis and as predictors of death and should be considered in the clinical care of these patients.

Haematological adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukaemia: A network meta-analysis.

AIMS: Despite their overall favourable safety profile, tyrosine kinase inhibitors (TKIs) are related to severe adverse events including haematological toxicities such as anaemia, leucopenia, neutropenia and thrombocytopenia. We designed a systematic review and network meta-analysis of randomised controlled trials to compare safety among TKIs (bosutinib, dasatinib, imatinib, nilotinib, ponatinib and radotinib) used by patients diagnosed with chronic myeloid leukaemia. METHODS: We obtained data from the PubMed, Scopus, Web of Science, and SciELO databases. The Bayesian approach was used for direct and indirect comparisons, and the treatments were ranked by the surface under the cumulative ranking curve (SUCRA). RESULTS: Seventeen studies were included in the network meta-analysis. Our data show that dasatinib was generally considered worse than the other TKIs, with SUCRA values ​​for 140 mg dasatinib of 90.3% for anaemia, 87.4% for leucopenia, 90.6% for neutropenia and 97.2% for thrombocytopenia. In addition, nilotinib was shown to be safer, with SUCRA values ​​for 600 and 800 mg doses of 21.9 and 35.8% for anaemia, 23.8 and 14.6% for leucopenia, 33.0 and 17.7% for neutropenia, and 28.7 and 32.6% for thrombocytopenia, respectively. CONCLUSION: Dasatinib appeared as the least safe drug for chronic myeloid leukaemia, probably because it binds to multiple key kinase targets, being more prone to cause serious haematological adverse events. Nilotinib demonstrated a safer profile, mostly due to its selective binding capacity.

Comparative efficacy and safety of systemic antifungal agents for candidemia: a systematic review with network meta-analysis and multicriteria acceptability analyses.

AIM: Invasive candidiasis is the most common fungal infection in patients attending health services and is associated with high mortality rates and prolonged hospital stay. The aim of this review was to evaluate and compare efficacy and safety of antifungal agents for the treatment of candidemia. METHODS: A systematic review with network meta-analysis (NMA), surface under the cumulative ranking analysis (SUCRA) and stochastic multicriteria acceptability analyses (SMAA) was performed (PROSPERO-CRD42020149264). Searches were conducted in PubMed and Scopus (Nov-2021). Randomised controlled trials evaluating the effect of oral antifungals (any dose or regimen) on mycological cure, discontinuation rates and adverse events were included. RESULTS: Overall, 13 trials (n=3632) were analysed. There were no significant differences between therapies for the efficacy outcomes; however, caspofungin (50-150 mg), rezafungin (200-400 mg) and micafungin (100-150 mg) had higher rates of clinical and mycological responses (SUCRA overall response >60%) and were considered the most promising therapies. Fluconazole (400 mg) rated worst for overall response (17%). Rezafungin (200-400 mg) and micafungin (100 mg) were associated with lower discontinuation rates (<40%). Conventional amphotericin B (0.6-0.7 mg/kg) was more likely to be discontinued (odds ratio [OR] 0.08; 95% credibility interval [CrI] 0.00-0.95 vs. caspofungin 150 mg) and may impair liver function (87%). CONCLUSION: Echinocandins are recommended as first-line treatments for invasive candidiasis following a priority order of caspofungin then micafungin. Rezafungin, an echinocandin under development, represents a potential option that should be further investigated. Azoles and liposomal amphotericin B can be used as second-line treatments in cases of fungal resistance or hypersensitivity.

Influence of foods and nutrients on COVID-19 recovery: A multivariate analysis of data from 170 countries using a generalized linear model.

BACKGROUND & AIMS: COVID-19 is an emergency public health problem of global importance. This study aimed to investigate the effect of foods and nutrients as complementary approaches on the recovery from COVID-19 in 170 countries, especially considering the complexity of the disease and the current scarcity of active treatments. METHODS: A retrospective study was performed using the Kaggle database, which links the consumption of various foods with recovery from COVID-19 in 170 countries, using multivariate analysis based on a generalized linear model. RESULTS: The results showed that certain foods had a positive effect on recovery from COVID-19: eggs, fish and seafood, fruits, meat, milk, starchy roots, stimulants, vegetable products, nuts, vegetable oil and vegetables. In general, consumption of higher levels of proteins and lipids had a positive effect on COVID-19 recovery, whereas high consumption of alcoholic beverages had a negative effect. In developed countries, where hunger had been eradicated, the effect of food on recovery from COVID-19 had a greater magnitude than in countries with a higher global hunger index (GHI), where there was almost no identifiable effect. CONCLUSION: Several foods had a positive effect on COVID-19 recovery in developed countries, especially food groups with a higher content of lipids, proteins, antioxidants and micronutrients (e.g., selenium and zinc). In countries with extreme poverty (high GHI), foods presented little effect on recovery from COVID-19.

Lag times in the publication of network meta-analyses: a survey.

OBJECTIVE: We assessed the extent of lag times in the publication and indexing of network meta-analyses (NMAs). STUDY DESIGN: This was a survey of published NMAs on drug interventions. SETTING: NMAs indexed in PubMed (searches updated in May 2020). PRIMARY AND SECONDARY OUTCOME MEASURES: Lag times were measured as the time between the last systematic search and the article submission, acceptance, online publication, indexing and Medical Subject Headings (MeSH) allocation dates. Time-to-event analyses were performed considering independent variables (geographical origin, Journal Impact Factor, Scopus CiteScore, open access status) (SPSS V.24, R/RStudio). RESULTS: We included 1245 NMAs. The median time from last search to article submission was 6.8 months (204 days (IQR 95-381)), and to publication was 11.6 months. Only 5% of authors updated their search after first submission. There is a very slightly decreasing historical trend of acceptance (rho=-0.087; p=0.010), online publication (rho=-0.080; p=0.008) and indexing (rho=-0.080; p=0.007) lag times. Journal Impact Factor influenced the MeSH allocation process, but not the other lag times. The comparison between open access versus subscription journals confirmed meaningless differences in acceptance, online publication and indexing lag times. CONCLUSION: Efforts by authors to update their search before submission are needed to reduce evidence production time. Peer reviewers and editors should ensure authors' compliance with NMA standards. The accuracy of these findings depends on the accuracy of the metadata used; as we evaluated only NMA on drug interventions, results may not be generalisable to all types of studies.

Systematic review with meta-analysis of the accuracy of diagnostic tests for COVID-19.

OBJECTIVE: To collate the evidence on the accuracy parameters of all available diagnostic methods for detecting SARS-CoV-2. METHODS: A systematic review with meta-analysis was performed. Searches were conducted in Pubmed and Scopus (April 2020). Studies reporting data on sensitivity or specificity of diagnostic tests for COVID-19 using any human biological sample were included. RESULTS: Sixteen studies were evaluated. Meta-analysis showed that computed tomography has high sensitivity (91.9% [89.8%-93.7%]), but low specificity (25.1% [21.0%-29.5%]). The combination of IgM and IgG antibodies demonstrated promising results for both parameters (84.5% [82.2%-86.6%]; 91.6% [86.0%-95.4%], respectively). For RT-PCR tests, rectal stools/swab, urine, and plasma were less sensitive while sputum (97.2% [90.3%-99.7%]) presented higher sensitivity for detecting the virus. CONCLUSIONS: RT-PCR remains the gold standard for the diagnosis of COVID-19 in sputum samples. However, the combination of different diagnostic tests is highly recommended to achieve adequate sensitivity and specificity.

Prognostic Factors, Survival Analyses and the Risk of Second Primary Cancer: A Population-Based Study on Burkitt Lymphoma/Leukemia.

Burkitt lymphoma/leukemia (BL/L) is an aggressive oncohematological disease. This study evaluated the population-based prognosis and survival on BL/L as well as if BL/L behaved as a risk factor for the development of second primary cancers (SPCs) and if other first tumors behaved as risk factors for the occurrence of BL/L as an SPC. A retrospective cohort using the Surveillance, Epidemiology and End Results (SEER) Program (2008-2016) was performed. Kaplan-Meier, time-dependent covariate Cox regression and Poisson regression models were conducted. Overall, 3094 patients were included (median, 45 years; IQR, 22-62). The estimated overall survival was 65.4 months (95% CI, 63.6-67.3). Significantly more deaths occurred for older patients, black race, disease at an advanced stage, patients without chemotherapy/surgery and patients who underwent radiotherapy. Hodgkin lymphomas (nodal) (RR, 7.6 (3.9-15.0; p < 0.001)), Kaposi sarcomas (34.0 (16.8-68.9; p < 0.001)), liver tumors (3.4 (1.2-9.3; p = 0.020)) and trachea, mediastinum and other respiratory cancers (15.8 (2.2-113.9; p = 0.006)) behaved as risk factors for the occurrence of BL/L as an SPC. BL/L was a risk factor for the occurrence of SPCs as acute myeloid leukemias (4.6 (2.1-10.4; p < 0.001)), Hodgkin lymphomas (extranodal) (74.3 (10.0-549.8; p < 0.001)) and Kaposi sarcomas (35.1 (12.1-101.4; p < 0.001)). These results may assist the development of diagnostic and clinical recommendations for BL/L.

Occurrence of antibiotics and antibiotic resistant bacteria in subtropical urban rivers in Brazil.

The occurrence of antibiotics in the natural environment has been a growing issue and correlations between this presence and developing resistance bacteria are explored. The purpose of this study was to investigate the presence of antibiotics of different classes and associated resistant bacteria, in water samples taken from urban river waters in Curitiba, Brazil. A method for the quantification of antibiotics (azithromycin, amoxicillin, norfloxacin ciprofloxacin, doxycycline and sulfamethoxazole) was developed and validated using liquid chromatography coupled with mass spectrometry. To investigate and identify coliforms resistant to these antibiotics, we performed selective microbiological culturing techniques. We detected antibiotics in our water samples; concentrations ranged from 0.13 to 4.63 µg L-1, with the highest being amoxicillin at 4.63 µg L-1. In all water samples this study, antibiotic resistant bacteria were detected. Escherichia coli was resistant to amoxicillin, norfloxacin, ciprofloxacin, doxycycline and sulfamethoxazole. Strains producing ß-lactamase with extended spectrum (ESBL and AmpC) were also found in these isolates. Enterococcus spp. displayed resistance to norfloxacin and ciprofloxacin, and some isolates were resistant to vancomycin, gentamicin and streptomycin (complementary tests). No P. aeruginosa resistant strains were observed. It is possible these antibiotics came from domestic effluents and may be contributing to the spread of bacterial resistance.

Chemical composition, cytotoxicity, and antibacterial activity of propolis from Africanized honeybees and three different Meliponini species.

ETHNOPHARMACOLOGICAL RELEVANCE: Propolis extracts are widely used in traditional folk medicine and exhibit several properties such as antitumor, anti-inflammatory, and antimicrobial. However, these products have not been investigated in combination with medicines used in clinical practice. AIM OF THE STUDY: This study aimed to evaluate the chemical composition of propolis extracts from Apis mellifera scutellata and different Meliponini species and characterize their cytotoxicity against tumor cells, antibacterial effects, and interference with the actions of doxorubicin and gentamicin. MATERIALS AND METHODS: Chromatographic and spectrometric analyses were performed using ultra-high-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS). Propolis extracts were evaluated for cytotoxicity and synergism using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the antimicrobial activity was examined using the broth microdilution technique and synergism was investigated using checkerboard and time-kill assays. RESULTS: The chemical characterization revealed the presence of 63 compounds, and the extracts showed selective cytotoxicity against tumor cell lines. Propolis extracts of mandaçaia and mirim exerted selective synergistic cytotoxicity in combination with doxorubicin. Except for the tubuna extract, all evaluated extracts exhibited antibacterial effects on gram-positive strains. Mandaçaia and mirim extracts exerted a synergistic effect with gentamicin; however, only mandaçaia extract exerted a selective effect. CONCLUSION: Propolis could be a source of antineoplastics and antibiotics. These natural products may reduce the occurrence of doxorubicin and gentamicin related adverse effects, resistance, or both.

Consumption of latex from Euphorbia tirucalli L. promotes a reduction of tumor growth and cachexia, and immunomodulation in Walker 256 tumor-bearing rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia tirucalli L. is an African plant that grows well in Brazil. Individuals diagnosed with cancer frequently consume latex from E. tirucalli, dissolved in drinking water. In vitro studies confirm the antitumor potential of E. tirucalli latex, but in vivo evaluations are scarce. AIM OF THE STUDY: To evaluate the effect of intake of an aqueous solution of E. tirucalli latex on tumor growth, cachexia, and immune response in Walker 256 tumor-bearing rats. MATERIALS AND METHODS: Latex from E. tirucalli was collected and analyzed by LC-MS. Sixty male Wistar rats (age, 90 days) were randomly divided into four groups: C, control group (without tumor); W, Walker 256 tumor-bearing group; SW1, W animals but treated with 25 µL latex/mL water; and SW2, W animals but treated with 50 µL latex/mL water. Animals received 1 mL of latex solution once a day by gavage. After 15 d, animals were euthanized, tumor mass was determined, and glucose and triacylglycerol serum levels were measured by using commercial kits. Change in the body weight during tumor development was calculated, and proliferation capacity of tumor cells was assessed by the Alamar Blue assay. Phagocytosis and superoxide anion production by peritoneal macrophages and circulating neutrophils were analyzed by enzymatic and colorimetric assays. Data are analyzed by one-way ANOVA followed by Tukey's post-hoc test, with the significance level set at 5%. RESULTS: The analysis of the latex revealed the presence of triterpenes. The ingestion of the latex aqueous solution promoted 40% and 60% reduction of the tumor mass in SW1 and SW2 groups, respectively (p < 0.05). The proliferative capacity of tumor cells from SW2 group was 76% lower than that of cells from W group (p < 0.0001). Animals treated with latex gained, on average, 20 g (SW1) and 8 g (SW2) weight. Glucose and triacylglycerol serum levels in SW1 and SW2 animals were similar to those in C group rats. Peritoneal macrophages and blood neutrophils from SW1 and SW2 animals produced 30-40% less superoxide anions than those from W group animals (p < 0.05), but neutrophils from SW2 group showed an increased phagocytic capacity (20%, vs. W group). CONCLUSIONS: E. tirucalli latex, administered orally for 15 d, efficiently reduced tumor growth and cachexia in Walker 256 tumor-bearing rats. Decreased tumor cell proliferative capacity was one of the mechanisms involved in this effect. Further, the data suggest immunomodulatory properties of E. tirucalli latex. The results agree with folk data on the antitumor effect of latex ingestion, indicating that it may be useful as an adjunct in the treatment of cancer patients. For this, further in vivo studies in animal and human models need to be conducted.

Antidiabetic potential of Musa spp. inflorescence: a systematic review.

OBJECTIVES: Extracts of parts Musa spp. have been used for the treatment of various diseases in traditional medicine. Studies have shown that these extracts have hypoglycaemic properties. The aim of this work was to gather evidence on the antidiabetic effects of Musa spp. inflorescence. METHODS: A systematic review was conducted with searches in three electronic databases, along with manual searches. Studies evaluating the antidiabetic properties of extracts of flower or bract of the genus Musa (in vitro or in vivo) were included. KEY FINDINGS: Overall, 16 studies were found. The reported assays were of hypoglycaemic effects, oral glucose tolerance, inhibitory activities in carbohydrate metabolism and digestive enzymes, enhanced glucose uptake activity and popular use of the extract in patients with diabetes type 2. In vitro studies showed that use of the extract was associated with antidiabetic effects (e.g. increased glucose uptake and inhibition of carbohydrate digestion enzymes). In induced diabetic models, Musa spp. extracts showed dose-dependent glycaemic level reductions compared with pharmacological drugs (P < 0.05). SUMMARY: In general, promising results regarding antidiabetic activity were found for inflorescence of Musa spp., suggesting that this plant could represent a natural alternative therapy for treating diabetes mellitus type 2.

Comparative efficacy and safety of tyrosine kinase inhibitors for chronic myeloid leukaemia: A systematic review and network meta-analysis.

BACKGROUND: The pharmacotherapy of chronic myeloid leukaemia (CML) is mainly based on tyrosine kinase inhibitors (TKIs). The aim of this study was to compare the efficacy and safety of all TKIs in CML patients. METHODS: We conducted a systematic review with network meta-analysis (NMA) of randomised controlled trials (RCTs), including imatinib, nilotinib, dasatinib, bosutinib, radotinib and ponatinib. Searches were performed in PubMed, Scopus, Web of Science and SciELo (March 2018). The NMAs were built for six outcomes at 12 months: complete cytogenetic response (CCyR), major cytogenetic response (MCyR), deep molecular response, major molecular response (MMR), complete haematologic response and incidence of serious adverse events. We conducted rank order and surface under the cumulative ranking curve (SUCRA) analyses. RESULTS: Thirteen RCTs were included (n = 5079 patients). Statistical differences were observed for some comparisons in all outcomes. Imatinib 400 mg was considered the safest drug (SUCRA values of 10.3%) but presented low efficacy. Overall, nilotinib 600 mg was superior to the other TKI in efficacy (SUCRA values of 61.1% for CCyR, 81.0% for MMR, 90.0% for MCyR); however, no data on its safety profile at 12 months were reported. INTERPRETATION: Our results suggest that nilotinib should be upgraded to first-line therapy for CML, although further cost-effectiveness analyses, including the new TKI (i.e., ponatinib, radotinib), are needed.